Abstract Fabry disease, an uncommon disease caused by deficiency of lysosomal enzyme ?-galactosidase A, leads to intracellular accumulation of its substrates, mainly globotriaosylceramide (GL3), causing severe multi-organ complications. Enzyme replacement therapy (ERT) is the current standard treatment for patients with Fabry disease. However, some cells, including kidney podocytes (PC), cardiac myocytes (CM) and vascular smooth muscle cells (VSMC), are relatively resistant to ERT, this creating residual risks in a substantial proportion of ERT treated patients for serious complications, such as stroke, heart and renal failure. While cardiovascular complications are the most common, and renal complications the next most common, cause of death in Fabry disease, the pathophysiology of the lesions underlying these complications is poorly understood and requires further studies. Such studies need access to large number of patients and biopsies and detailed clinical information, these being common roadblocks in the study of rare diseases. The Lysosomal Disease Network (LDN) has created a unique opportunity of networking among the investigators studying such rare diseases. Using our extensive network of collaborators inside and outside of LDN as well as our own rich cardiac, renal, and skin biopsy collections, we are extremely well poised to study the natural history and ERT treatment outcomes of the key lesions of cardiovascular and renal complications of Fabry disease through novel morphometric approaches that we have developed. These validated specific and quantitative approaches will allow us to describe the relationships between these lesions and cardiac and renal function. We will also study skin arteriolar VSMC including in patients with concomitant renal biopsies in order to determine if a less invasive approach will provide vital organ information regarding these important cells in less accessible tissues. In addition, we will study the effect of ERT on GL3 clearance from cardiac myocytes and cardiac, renal and skin VSMC so as to determine factors influencing the effectiveness of ERT. These studies are highly likely to provide reproducible and sensitive structural endpoints for future Fabry disease clinical trials exploring new treatment approaches. In addition, we will assess tilt table variability of heart rate and blood pressure response, as well as electrocardiographic (ECG) markers of ventricular depolarization/repolarization in order to detect the presence and severity of dysautonomia in Fabry disease and, in pilot studies, to test whether these dysautonomia and ECG parameters can predict the development of cardiac events/dysfunction in Fabry patients. These unique cardiac and renal projects are highly likely to lead to new insights furthering our understanding of Fabry disease and to new clinical trial strategies.